Anemia is prevalent in patients with chronic kidney disease (CKD) and is associated with lower quality of life and higher risk of adverse outcomes, including cardiovascular disease and death. Several modes of anemia management in patients with CKD involve the use of erythropoiesis-stimulating agents (ESA), supplemental oral and intravenous iron and blood transfusions. However, many patients do not respond adequately to these treatments or require higher doses of ESA and/or iron. High doses of iron may also cause toxicity associated with generation of oxygen radicals and allergic reactions. These treatments may lack efficacy because they do not fully address the underlying cause of the anemia, i.e., impaired iron absorption and iron mobilization from body stores.
Attempts to manage erythropoietin resistance are currently performed by the co-administration of high dose parenteral iron. However, most iron from intravenous preparations is first processed by macrophages, and its utilization for erythropoiesis is dependent on ferroportin-mediated iron export.
In many anemia patients, ferroportin-mediated iron export is suppressed by high levels of hepcidin. Additional evidence suggests that increased levels of hepcidin correlate with poor ESA responsiveness in hemodialysis. Hepcidin-lowering agents may therefore be an effective strategy for ameliorating ESA-refractory anemia in this patient population and in other forms of anemia of chronic disease (ACD) characterized by iron restriction.
Therefore, methods that decrease circulating hepcidin levels should enhance iron absorption, facilitate release of sequestered iron, and promote erythropoiesis in ESA-refractory anemia present in chronic kidney disease patients.
Despite current treatment options for treating diseases and disorders associated anemia, there remains a need for improved compositions for treatments of anemia which are effective and well-tolerated.